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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/E1051    most recent 00689.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Roy, C. Articles by Cianflone, K. PubMed PubMed Citation Articles by Roy, C. Articles by Cianflone, K.

Shift in metabolic fuel in acylation-stimulating protein-deficient mice following a high-fat diet

¹Centre de Recherche Hôpital Laval, Université Laval, Quebec; ²Department of Biochemistry, McGill University, Montreal, Quebec, Canada; ³Department of Human Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands; ⁴Division de Kinésiologie, Départment de Médecine Sociale et Préventive, Université Laval, Ste-Foy, Quebec, Canada; and ⁵Department of Human Movement Sciences, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands

Submitted 25 October 2007 ; accepted in final form 26 March 2008

ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (–39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (–25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (–31%, P = 0.005), hexokinase (–43%, P = 0.007), phosphofructokinase (–51%, P < 0.0001), and GAPDH (–15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (–48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.

muscle metabolism; glycolysis; β-oxidation; C3adesArg